Stimulation of food intake is important in connection with patients suffering from anorexia due to chronic medical conditions, eating disorders, and other conditions in which excessive weight loss has produced a detrimental effect on the patients' health.
Obesity is a common and very serious public health problem as it increases a person's risk for a number of serious conditions, including diabetes, heart disease, stroke, high blood pressure, and some types of cancers. Considerable increase in the number of obese individuals over the past two decades has created profound public health implications. Although studies have demonstrated that reduction in obesity by diet and exercise reduces the associated risk factors dramatically, these treatments are largely unsuccessful considering obesity is strongly associated with genetically inherited factors that contribute to increased appetite, preferences for highly caloric foods, reduced physical activity, and increased lipogenic metabolism.
Growth hormone (GH) is not only of importance for linear body growth but is also of major importance for the maintenance of body composition, metabolism and heart function in adult life. GH release from the anterior pituitary is regulated by the stimulatory peptide GH-releasing hormone (GHRH) and the inhibitory peptide somatostatin (Frohman, L; Jansson, J.-O. Endocr. Rev. (1986) 7:223–253). Early research identified small GH-releasing peptides (GHRPs) derived from the pentapeptide met-enkephalin (Momany, F; Browers, C, et al: Endocrinology (1981) 108:31–39). Further efforts led to the development of a number of peptidyl and non-peptidyl growth hormone secrectgogues (GHSs), including the orally-active, non-peptidyl GH secretagogue MK677 (Svensson, J; Lohn, L; Jansson, J.-O. et al: J. Clin. Endocrinol. Metab. (1998) 83:362–369). Later efforts cloned a seven-transmembrane GPCR that was a target for the GHSs (Howard, A; Feighner, S.; Cully, D. et al: Science (1996) 273:974–977).
This GHS-receptor (GHS-R) is localized in the hypothalamus and in the pituitary, but also in other brain areas such as the hippocampus as well as the pancreas. Recently, an endogenous ligand for the GHS-R, ghrelin, an acylated peptide consisting of 28 amino acids was isolated (Kojima, M; Hosoda, H; Date, Y; Nakazoto, M.; Matsuo, H; Kangawa, K: Nature (1999), 402:656–660). Since then, ghrelin has been found to be localized in the hypothalamic-pituitary area where it stimulates the release of GH to the circulation, but is also found in the highest concentration in the stomach.
Biological evidence indicates that ghrelin has an important role in the regulation of metabolism and energy expenditure. Ghrelin was found to stimulate food intake and weight gain when administered either systemically or intraventricularly in rodents (Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. Nature 2001;409:194–198) (Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, et al. Gastroenterology 2001;120:337–345). Ghrelin was also found to be more potent than any other orexigenic peptide except neuropeptide Y (NPY). The orexigenic activity of centrally administered ghrelin is thought to be mediated by brain NPY and AGRP, two neuropeptides with potent orexigenic actions (Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Endocrinology 2000;141:4797–4800). It was also recognized that the appetite activity of centrally administered ghrelin can be blocked by co administration of a NPY-Y1 receptor antagonist. In addition, ghrelin was found to reverse leptin-induced inhibition of food intake (Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, et al. Diabetes 2001;50:227–232). Ghrelin exerts its actions in the arcuate nucleus and paraventricular nucleus to influence the interplay of NPY, AGRP and a-MSH circuits. Ghrelin may also act via afferent vagal pathways that terminate in the hypothalamus. In obese patients, the increase in the plasma ghrelin level with diet-induced weight loss is consistent with the hypothesis that ghrelin has a role in the long-term regulation of body weight. Gastric bypass in obese patients is associated with markedly suppressed ghrelin levels, possibly contributing to the weight-reducing effect of the procedure (Cummings, D. E. et al: N Engl J Med 2002;346:1623–30).
Intracerebroventricular treatment with the anti-ghrelin antiserum against the N-terminal region twice a day for 5 days in rats decreased significantly both daily food intake and body weight (Murakami, N; T Hayashida, T; T Kuroiwa, T; K Nakahara, K; Ida, T; Mondal, M S; Nakazato, M; Kojima M; Kangawa, K. Journal of Endocrinology (2002) 174, 283–288). Transgenic (Tg) rats expressing an antisense ghrelin receptor mRNA under the control of the promoter for tyrosine hydroxylase (TH) selectively attenuated ghrelin receptor protein expression in the arcuate nucleus (Arc). Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats (Shuto, Y; Shibasaki, T; Otagiri, A; et al: J. Clin. Invest. 109:1429–1436 (2002)). These data suggest that ghrelin receptor modulators may be beneficial in the treatment of anorexia, cancer cachexia, eating disorders, age-related decline in body composition, weight gain, obesity and disorders associated with obesity such as diabetes mellitus.